53BP1 facilitates long-range DNA end-joining during V(D)J recombination.
Variable, diversity and joining (V(D)J) recombination and class-switch recombination use overlapping but distinct non-homologous end joining pathways to repair DNA double-strand-break intermediates. 53BP1 is a DNA-damage-response protein that is rapidly recruited to sites of chromosomal double-strand breaks, where it seems to function in a subset of ataxia telangiectasia mutated (ATM) kinase-, H2A histone family member X (H2AX, also known as H2AFX)- and mediator of DNA damage checkpoint 1 (MDC1)-dependent events. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination. Here we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1-deficient lymphocytes that is distinct from that found in classical non-homologous-end-joining-, H2ax-, Mdc1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of unrepaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes that have antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks.
Difilippantonio
Simone
S
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1360, USA.
Gapud
Eric
E
Wong
Nancy
N
Huang
Ching-Yu
CY
Mahowald
Grace
G
Chen
Hua Tang
HT
Kruhlak
Michael J
MJ
Callen
Elsa
E
Livak
Ferenc
F
Nussenzweig
Michel C
MC
Sleckman
Barry P
BP
Nussenzweig
André
A
D000818:Animals; D017209:Apoptosis; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053960:DNA Breaks; D004268:DNA-Binding Proteins; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics*; D019673:Genes, T-Cell Receptor alpha / Q000235:genetics; D042822:Genomic Instability; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008231:Lymphopenia / Q000235:genetics / Q000473:pathology; D051379:Mice; D008957:Models, Genetic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D017385:Sequence Homology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D000071857:Tumor Suppressor p53-Binding Protein 1
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA